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X-ray structures of magnesium and manganese complexes with the N-terminal domain of calmodulin: Insights into the mechanism and specificity of metal ion binding to an EF-hand

Biochemistry, ISSN: 0006-2960, Vol: 51, Issue: 31, Page: 6182-6194
2012
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Calmodulin (CaM), a member of the EF-hand superfamily, regulates many aspects of cell function by responding specifically to micromolar concentrations of Ca in the presence of an ∼1000-fold higher concentration of cellular Mg. To explain the structural basis of metal ion binding specificity, we have determined the X-ray structures of the N-terminal domain of calmodulin (N-CaM) in complexes with Mg, Mn, and Zn. In contrast to Ca, which induces domain opening in CaM, octahedrally coordinated Mg and Mn stabilize the closed-domain, apo-like conformation, while tetrahedrally coordinated Zn ions bind at the protein surface and do not compete with Ca . The relative positions of bound Mg and Mn within the EF-hand loops are similar to those of Ca; however, the Glu side chain at position 12 of the loop, whose bidentate interaction with Ca is critical for domain opening, does not bind directly to either Mn or Mg, and the vacant ligand position is occupied by a water molecule. We conclude that this critical interaction is prevented by specific stereochemical constraints imposed on the ligands by the EF-hand β-scaffold. The structures suggest that Mg contributes to the switching off of calmodulin activity and possibly other EF-hand proteins at the resting levels of Ca. The Mg-bound N-CaM structure also provides a unique view of a transiently bound hydrated metal ion and suggests a role for the hydration water in the metal-induced conformational change. © 2012 American Chemical Society.

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